Biomarker-guided duration of antibiotic treatment for sepsis [COVID-19] [UPH]
Research type
Research Study
Full title
Biomarker-guided duration of antibiotic treatment in hospitalised patients with suspected sepsis. The ADAPT-Sepsis Trial.
IRAS ID
209815
Contact name
Paul Dark
Contact email
Sponsor organisation
University of Manchester
ISRCTN Number
ISRCTN47473244
Duration of Study in the UK
3 years, 11 months, 30 days
Research summary
Sepsis is a common life-threatening condition that is triggered by infection. In sepsis, the body’s defence mechanisms (immune system) react excessively, resulting in widespread inflammation and swelling. If not treated quickly, sepsis can result in shutdown of vital organs which can result in death. Each year in the UK, about 200,000 people develop sepsis and up to a quarter will die. Previous research indicate that early recognition of sepsis and rapid antibiotic treatments are the most important factors for patient survival. While starting antibiotics for sepsis is crucial, the recommended duration of such treatment is uncertain. The lack of research on when to stop treatment safely can lead to an overuse of antibiotics in this condition. Antibiotic overuse is important because it promotes bacteria that are resistant to antibiotics (antimicrobial resistance), which means that sepsis and, indeed, other infections would become difficult to treat in the future. Shorter courses of antibiotics for a patient with sepsis, if given appropriately, may result in less antibiotic use resulting in fewer side effects, less risk of antibiotic resistance and a reduction in costs. Chemicals circulating in the blood can indicate the level of an infection and how effective the treatment of an infection is. These chemicals are called biomarkers. The two most well researched circulating biomarkers in sepsis are C-reactive protein (CRP) and procalcitonin (PCT). They are both protein chemicals produced by the human body in response to infection and can be readily measured in blood samples using NHS laboratory equipment. The aim of this study is to find out whether the duration of antibiotic treatment given to patients with sepsis can be safely reduced following the close daily monitoring of these biomarkers. Patients will have blood samples taken daily whilst receiving antibiotic treatment (typically 7 days), follow-up at 28 & 90 days.
Lay summary of study results:
ADAPT-Sepsis Final Report – Plain English Background Sepsis is a common life-threatening condition that is triggered by infection. In sepsis, the body’s defence mechanisms (immune system) react excessively, resulting in widespread inflammation and swelling. If not treated quickly, sepsis can result in the shutdown of vital organs which can result in death.
Each year in the UK, more than 100,000 people are admitted to hospital with sepsis and around 37,000 will die. Earlier research indicates that early recognition of sepsis and rapid antibiotic treatments are the most crucial factors for patient survival.
Many patients with sepsis are treated in intensive care units in hospitals where they be provided with high levels of skilled clinical care.
The human body naturally has certain organic compounds that can be measured in laboratories. The level of some of these compounds – called biomarkers – change when there is an infection. The levels of two in particular - called procalcitonin (PCT) and C-Reactive protein (CRP) - are raised when a person has sepsis. As a patient recovers from sepsis, these elevated levels fall.
The normal, or standard, treatment of sepsis is a course of powerful antibiotics lasting seven days or more. Whilst this is normally successful, it is not without risk to the patient and excessive or unnecessary use of antibiotics can lead to the increased risk of antibiotic resistance. Antibiotic resistance can make the treatment of other infections more difficult. A trial was therefore developed that explored whether the regular measuring of the PCT and CRP biomarkers could lead to the reduced use of antibiotics and improved outcomes for patients.
The TrialThe Trial was designed to determine whether the regular monitoring of PCT or CRP compared with standard care in critically ill patients with sepsis could lead to reduced antibiotic use without compromising patient safety or outcomes.
The Trail was conducted in a total of 41 hospitals between January 2018 and July 2024. It was paused between March 2020 and August 2020 during the COVID-19 pandemic. Not all the hospitals that were taking part before this closure rejoined afterwards but new ones were subsequently recruited. These hospitals ranged in size from relatively small district general hospitals to large, multi-specialist teaching centres and were located throughout the United Kingdom.
A total of 2760 patients were recruited to the trial randomly allocated to one of three trial arms –one for the measuring PCT levels (a total of 918 patients), one measured CRP levels (a total of 924 patients) and one provided standard care (a total of 918 patients). All the patients were over 18 years of age, likely to still be in hospital and receiving antibiotics intravenously for at least 72 hours and had been identified within 24 hours of first receiving antibiotic treatment. Each patient was randomly allocated to one of the arms by an automated computer system run through the Warwick University Clinical Trials Unit (Warwick CTU). The primary aim of the Trial was to assess the use of antibiotics up to 28 days from the day that the patient enrolled in the Trial. Patients were, however, continued to be monitored for up to 90 days so that clinical outcomes could be monitored and compared.
Methods
The Trial required that a sample of blood be taken daily from each participant and sent to the local NHS quality assured biomarker testing laboratory. For those patients in the PCT and CRP arms, known as the ‘intervention arms,’ the sample was tested, and these results were entered into a database hosted at the Warwick CTU. Samples from those in the standard care arm were not tested for biomarkers but were still tested for other relevant conditions such as white blood cell count. In all cases, the clinicians treating the patients received standardised reports that, in the case of the intervention arms, recommended continuing or discontinuing the use of antibiotics. The guidance was informed by the reported levels of the biomarker. In the case of those in the standard care arm, the recommendation was for a continuation of standard care. The treating clinician was not, however, aware of the particular arm that the patient was in.Results
Compared with the standard care, there was a consistent average reduction in the use of antibiotics in those patients whose levels of PCT were monitored but no significant reduction was identified for those whose CRP levels were monitored. This reduction amounted to an average of 1 day of antibiotics per patient for an average of 10 days of antibiotics used for sepsis up to 28 days. Although this 10% saving in antibiotics may seem a modest reduction, considering the number of critically ill patients with sepsis that are treated each year across the UK, the reduction equates to a meaningful reduction in the use of antibiotics in patients with sepsis.In terms of patient safety, there were no detectable differences in patient morbidity or mortality at either 28 or 90 days between any of the three arms.
This report focusses on the clinical aspects of the Trial. A further report is to be prepared in due course that considers health economics and procedural aspects.
Conclusion
Sepsis patient care guided by measurement of PCT reduces antibiotic duration safely compared with standard care, but CRP does not.
URL to summary results: https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Ftrack.pstmrk.it%2F3ts%2Fwww.isrctn.com%252FISRCTN47473244%2FNBTI%2FRHO_AQ%2FAQ%2F6db44e66-2f25-4f2e-8509-ba648f6e2d82%2F2%2FvIwewYCoV6&data=05%7C02%7CTracy.Hamrang%40hra.nhs.uk%7Cd90205c14a59401e1c8608ddd015ed47%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638895514767157013%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=3%2B8UURat3L8%2Ff1p8nKVHvSbDKV9y3iFAWfdJTjGQKaE%3D&reserved=0REC name
South Central - Oxford C Research Ethics Committee
REC reference
17/SC/0434
Date of REC Opinion
6 Sep 2017
REC opinion
Favourable Opinion